Process for the preparation of 4-amino-5-fluoro-3-chloro-6-(substituted)picolinates

ABSTRACT

4-Amino-5-fluoro-3-chloro-6-(substituted)picolinates are prepared from trifluoroacetic acid, p-methoxyaniline, a C 1 -C 4  alkyl propiolate and a substituted methylene amine by a series of steps.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent Ser. No. 15/040,577,filed on Feb. 10, 2016, U.S. Pat. No. 14/104,127, filed on Dec. 12,2013, and claims the benefit of U.S. Provisional Patent Application Ser.No. 61/736,841 filed Dec. 13, 2012, the disclosure of which is expresslyincorporated herein by reference.

FIELD

Provided herein are processes for the preparation of4-amino-5-fluoro-3-chloro-6-(substituted)picolinates. More particularly,provided herein are processes for the preparation of4-amino-5-fluoro-3-chloro-6-(substituted)picolinates from a non-pyridinesource.

BACKGROUND

U.S. Pat. Nos. 6,784,137 B2 and 7,314,849 B2 describe inter alia certain4-amino-5-fluoro-3-chloro-6-(aryl)picolinate compounds and their use asherbicides. U.S. Pat. No. 7,432,227 B2 describes inter alia certain4-amino-5-fluoro-3-chloro-6-(alkyl)picolinate compounds and their use asherbicides. Each of these patents describes the manufacture of4-amino-5-fluoro-3-chloropicolinate starting materials by fluorinationof the corresponding 5-unsubstituted pyridines with1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate). Each of these patents also describes themanufacture of 6-(aryl)-4-aminopicolinates from coupling reactionsinvolving picolines having either a facile leaving group or a metalderivative in the 6-position of the picoline ring. It would beadvantageous to produce4-amino-5-fluoro-3-chloro-6-(substituted)picolinates without having torely on metal assisted couplings. It would be advantageous to produce4-amino-5-fluoro-3-chloro-6-(substituted)picolinates efficiently and inhigh yield from a non-pyridine source. It would also be advantageous toproduce 4-amino-5-fluoro-3-chloro-6-(substituted)picolinates withouthaving to rely on direct fluorination of the 5-position of the pyridinering with an expensive fluorinating agent like1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate).

SUMMARY

Provided herein are processes for the preparation of4-amino-5-fluoro-3-chloro-6-(substituted)picolinates from a non-pyridinesource without a metal assisted coupling and without fluorination withan expensive fluorinating agent like1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate). More particularly, provided herein are processesfor the preparation of a4-amino-5-fluoro-3-chloro-6-(substituted)picolinate of the Formula I

-   -   wherein    -   R¹ represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenyl        substituted with from 1 to 4 substituents independently selected        from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or        C₁-C₄ haloalkoxy, and    -   R² represents C₁-C₄ alkyl,        which comprises the following steps:

a) contacting trifluoroacetic acid with p-methoxyaniline in the presenceof a triarylphosphine and a trialkylamine base in carbon tetrachloridesolvent to produce an acetimidoyl chloride of Formula A

b) contacting the acetimidoyl chloride of Formula A with a C₁-C₄ alkylpropiolate (Formula B)

-   -   wherein R² is as previously defined,        in the presence of copper (I) iodide, an alkali metal iodide and        an alkali metal phosphate in a polar aprotic solvent to produce        an (imino)pent-2-ynoate of Formula C

c) cyclizing the (imino)pent-2-ynoate of Formula C with an amine ofFormula D

-   -   wherein R¹ is as previously defined,        in the presence of an inorganic alkali metal base in a polar        aprotic solvent at temperature from about ambient to about        100° C. to produce an alkyl        4-amino-5-fluoro-6-(substituted)-picolinate of Formula E

-   -   wherein R¹ and R² are as previously defined; and

d) halogenating and deprotecting the alkyl4-amino-5-fluoro-6-(substituted)picolinate of Formula E with1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (Formula F)

in the presence of a mineral acid in a polar solvent to produce the4-amino-5-fluoro-3-chloro-6-(substituted)picolinate of the Formula I.

Provided herein are also processes for the preparation of a4-amino-5-fluoro-3-chloro-6-(substituted)picolinate of the Formula I

-   -   wherein    -   R¹ represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenyl        substituted with from 1 to 4 substituents independently selected        from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or        C₁-C₄ haloalkoxy, and    -   R² represents C₁-C₄ alkyl,        which comprises halogenating and deprotecting an alkyl        4-amino-5-fluoro-6-(substituted)-picolinate of Formula E

-   -   wherein R¹ and R² are as previously defined,        with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (Formula        F)

in the presence of a mineral acid in a polar solvent to produce the4-amino-5-fluoro-3-chloro-6-(substituted)picolinate of the Formula I.

Another embodiment is a compound of Formula E

wherein

-   -   R¹ represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenyl        substituted with from 1 to 4 substituents independently selected        from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or        C₁-C₄ haloalkoxy, and    -   R² represents C₁-C₄ alkyl.

Another embodiment is a compound of Formula C

wherein

-   -   R² represents C₁-C₄ alkyl.

Another embodiment is a compound of Formula G

wherein

-   -   R¹ represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenyl        substituted with from 1 to 4 substituents independently selected        from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or        C₁-C₄ haloalkoxy, and    -   R² represents C₁-C₄ alkyl.

DETAILED DESCRIPTION

The term alkyl and derivative terms such as alkoxy, as used herein referto straight chain or branched chain groups. Typical alkyl groups aremethyl, ethyl, propyl, 1-methyl-ethyl, butyl, 1,1-dimethylethyl and1-methylpropyl. Methyl and ethyl are often preferred.

Unless specifically limited otherwise, the term “halogen,” as well asderivative terms such as “halo,” refers to fluorine, chlorine, bromineand iodine.

The phenyl groups substituted with from 1 to 4 substituentsindependently selected from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy or C₁-C₄ haloalkoxy may be of any orientation, but 4-substitutedphenyl, 2,4-disubstituted phenyl, 2,3,4-trisubstituted phenyl,2,4,5-trisubstituted phenyl, and 2,3,4,6-tetrasubstituted phenyl isomersare preferred.

Alkyl 4-amino-5-fluoro-3-chloro-6-(substituted)picolinates are preparedfrom trifluoroacetic acid, p-methoxyaniline, a C₁-C₄ alkyl propiolateand a substituted methylene amine by a series of steps.

In the initial step, trifluoroacetic acid is reacted withp-methoxyaniline and carbon tetrachloride in the presence of atriarylphosphine and a trialkylamine base to produce2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride. While oneequivalent of p-methoxyaniline is required for each equivalent oftrifluoroacetic acid, it is often convenient to use an excess of theaniline, typically a 10 to 20% excess. A similar excess of trialkylaminebase is also preferred. It is often convenient to use a much largerexcess of triarylphosphine, typically in the range of a 2 to 4 foldexcess. Carbon tetrachloride, while serving as a reactant, is alsoconveniently used as a solvent for the initial reaction. The reaction isexothermic and it is convenient to control the exotherm by externalcooling and the controlled addition of a carbon tetrachloride solutionof p-methoxyaniline to a mixture of trifluoroacetic acid, trialkylamineand triarylphosphine in carbon tetrachloride. After the initial exothermsubsides, the reaction mixture is generally heated to reflux until theconversion is complete.

In a typical reaction, a mixture of about 3 equivalents oftriphenylphosphine and trifluoroacetic acid in carbon tetrachloride iscooled to about 0° C. in an ice bath and a 20% excess of triethylamineis added. With continued cooling, about a 20% excess of p-methoxyanilinein carbon tetrachloride is slowly added. After completion of theaddition, the mixture is heated to about 70° C. for several hours. Aftercooling, the reaction mixture is extracted with hexane and the solventis evaporated to provide crude2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride.

In the second step, the 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoylchloride is coupled with a C₁-C₄ alkyl propiolate in the presence ofcopper (I) iodide, an alkali metal iodide and an alkali metal phosphatein a polar aprotic solvent to produce a C₁-C₄ alkyl5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate. While oneequivalent of C₁-C₄ alkyl propiolate is required for each equivalent ofacetimidoyl chloride, it is often convenient to use an excess of thepropiolate, typically a 10 to 20% excess. Similarly, a 10 to 20% molarexcess of alkali metal iodide and alkali metal phosphate are generallypreferred. While the reaction is catalytic in copper (I) iodide, usuallyabout 0.1 to about 0.3 equivalents are employed. The coupling reactionis conducted in a polar aprotic solvent at a temperature from about 40°C. to about 100° C. Preferred polar aprotic solvents include ethers liketetrahydrofuran, esters like ethyl acetate, nitriles like acetonitrile,amides like N,N-dimethylformamide and N-methyl pyrrolidinone andsulfoxides like dimethyl sulfoxide. Anhydrous solvents are preferredwith anhydrous acetonitrile being especially preferred.

In a typical reaction, 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoylchloride and a slight excess of methyl propiolate are mixed with about0.3 equivalents of copper (I) iodide and slight excesses of potassiumphosphate and potassium iodide in anhydrous acetonitrile. The mixture isheated at about 60° C. under a nitrogen atmosphere until the reaction iscomplete. After cooling, an extraction solvent like a halogenatedhydrocarbon is added to the mixture along with water. The organic layeris recovered, washed with brine and dried. The solvent is evaporated toprovide crude methyl5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate.

In the cyclization reaction, the5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate is reacted witha methylene amine substituted with an alkyl, cyclopropyl, alkenyl or(substituted)phenyl group in the presence of an inorganic alkali metalbase in a polar aprotic solvent to produce an alkyl4-(4-methoxyphenylamino)-5-fluoro-6-(substituted)picolinate. While oneequivalent of substituted methylene amine is required for eachequivalent of 5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate,it is often convenient to use an excess of the methylene amine,typically a 2 to 4 fold excess. Suitable inorganic alkali metal basesinclude the lithium, sodium, potassium and cesium salts of hydroxides,carbonates and phosphates. Cesium carbonate is particularly preferred.In general, it is convenient to use a 2 to 4 fold excess of theinorganic alkali metal base. Preferred polar aprotic solvents includeethers like tetrahydrofuran, esters like ethyl acetate, nitriles likeacetonitrile, amides like N,N-dimethylformamide andN-methylpyrrolidinone and sulfoxides like dimethyl sulfoxide. Anhydroussolvents are preferred with anhydrous tetrahydrofuran and dimethylsulfoxide being especially preferred. The reaction is typicallyconducted at a temperature from about ambient to about 100° C.

In a typical reaction, methyl5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate is mixed withabout a 2.5 to 3 fold excess of 4-chlorobenzyl amine and about a 2.5 to3 fold excess of cesium carbonate in anhydrous terahydrofuran. Themixture is heated at about 80° C. until the reaction is complete. Aftercooling, an extraction solvent like a halogenated hydrocarbon is addedto the mixture along with water. The organic layer is recovered, washedwith brine and dried. The solvent is evaporated to provide crude methyl4-(4-methoxyphenylamino)-5-fluoro-6-(4-chlorophenyl)picolinate.

The final step involves both the chlorination and the deprotection ofthe amino group by removal of the 4-methoxyphenyl substituent. An alkyl4-(4-methoxyphenylamino)-5-fluoro-6-(substituted)picolinate is reactedwith 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione in the presence ofa mineral acid in a polar solvent at a temperature from about ambient toabout 100° C. to produce an alkyl4-amino-5-fluoro-3-chloro-6-(substituted)picolinate. While oneequivalent of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione isrequired for each equivalent of alkyl4-(4-methoxyphenylamino)-5-fluoro-6-(4-chlorophenyl)picolinate, it isoften convenient to use an excess of the1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione, typically a 2 to 4fold excess. Suitable mineral acids include sulfuric and phosphoricacids with sulfuric acid being preferred. The mineral acids are usuallyused as aqueous solutions. Approximately one equivalent of mineral acidis required but a 10 to 30% excess is preferred. Thechlorination/deprotection is conveniently performed in a mixture of apolar solvent such as acetonitrile with water.

If the chlorination/deprotection reaction is performed in the absence ofthe mineral acid, an alkyl4-((4-oxocyclohexa-2,5-dien-1-ylidene)amino)-5-fluoro-6-(substituted)-picolinate(Formula G) is obtained without chlorination of the 3-position on thepyridine ring.

The alkyl 4-((4-oxocyclohexa-2,5-dien-1-ylidene)amino)-5-fluoro-6-(substituted)picolinate can be subsequentlyreacted with a mineral acid to deprotect the amino group and provide analkyl 4-amino-5-fluoro-6-(substituted)picolinate (Formula H).

In a typical reaction accomplishing both chlorination and deprotection,methyl 4-(4-methoxyphenylamino)-5-fluoro-6-(4-chlorophenyl)picolinate isreacted with about two equivalents of1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione in the presence of a 1M (molar) solution of sulfuric acid in a mixture of acetonitrile/water.The mixture is heated at reflux until the reaction is complete. Themixture is added to methylene chloride and the organic layer isseparated, washed with brine and dried. The solvent is evaporated toprovide crude methyl4-amino-5-fluoro-3-chloro-6-(4-chlorophenyl)picolinate.

The products obtained by any of these processes, can be recovered byconventional means, such as evaporation or extraction, and can bepurified by standard procedures, such as by distillation,crystallization or chromatography.

The described embodiments and following examples are for illustrativepurposes and are not intended to limit the scope of the claims. Othermodifications, uses, or combinations with respect to the compositionsdescribed herein will be apparent to a person of ordinary skill in theart without departing from the spirit and scope of the claimed subjectmatter.

EXAMPLES Example 1 2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidoylchloride

A mixture of triphenylphosphine (34.6 grams (g), 132.0 millimoles(mmol)), 2,2,2-trifluoroacetic acid (3.37 milliliters (mL), 44 mmol),triethylamine (7.38 mL, 53.0 mmol) and carbon tetrachloride (21.3 mL,220.0 mmol) was magnetically stirred while cooled with an ice bath.After 10 minutes (min), p-methoxyaniline (6.53 g, 53.0 mmol) dissolvedin carbon tetrachloride (21 mL, 220.0 mmol) was added slowly(exothermic). The ice bath was removed, and the reaction mixture wasstirred at reflux for 4 hours (h). Upon cooling to room temperature, thereaction mixture was washed with hexane (3×100 mL). Solvent was removedusing a rotary evaporator to give 9.8 g of an orange oil. Distillationgave 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride (9.31 g,39.2 mmol, 89% yield) as a light yellow liquid: by 75-77° C./0.3 mmHg;¹H NMR (400 MHz, CDCl₃) δ 7.31 (m, 2H), 6.96 (m, 2H), 3.84 (s, 3H); ¹³CNMR (101 MHz, CDCl₃) δ 159.56 (s), 135.45 (s), 127.98 (q), 124.35 (s),117.05 (q), 114.25 (s), 55.50 (s).

Example 2 Methyl 5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate

To a magnetically stirred solution of2,2,2-trifluoro-N-(4-methoxyphenyl)-acetimidoyl chloride (2.376 g, 10.00mmol) and methyl propiolate (1.009 g, 12.00 mmol) in anhydrousacetonitrile (CH₃CN; 20 mL) was added a ground-up mixture of copper(I)iodide (0.571 g, 3.00 mmol), potassium phosphate (2.55 g, 12.00 mmol)and potassium iodide (1.660 g, 10.00 mmol). After heating for 4 h at 60°C. under nitrogen, the reaction mixture was added to dichloromethane(CH₂Cl₂; 100 mL) and water (H₂O; 50 mL). The organic layer was washedwith a saturated solution of sodium chloride (NaCl) and dried (magnesiumsulfate (MgSO₄)), and the solvent was removed leaving 3.4 g of a darkbrown oil. The material was passed through a plug of silica gel elutingwith 5% ethyl acetate (EtOAc)/hexane to give methyl5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate (2.11 g, 7.40mmol, 74.0% yield) as an orange oil: ¹H NMR (400 MHz, CDCl₃) δ 7.54 (m,2H), 6.97 (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H); ¹³C NMR (101 MHz, CDCl₃)δ 161.11 (s), 152.43 (s), 138.87 (s), 131.88 (q), 125.46 (s), 118.70(q), 114.33 (s), 86.82 (s), 73.95 (s), 55.59 (s), 53.50 (s); HRMS-ESI(m/z) [M+H]⁺ calcd for C₁₇H₁₁ClF₃NO, 285.0613; found 285.0611.

Example 3 Methyl6-(4-chlorophenyl)-5-fluoro-4-((4-methoxyphenyl)amino)picolinate

A magnetically stirred solution of methyl5,5,5-trifluoro-4-(4-methoxyphenyl-imino)pent-2-ynoate (0.570 g, 2.0mmol), p-chlorobenzylamine (0.850 g, 6.00 mmol) and cesium carbonate(1.629 g, 5.00 mmol) in anhydrous terahydrofuran (THF; 10 mL) was heatedto 80° C. in a Discover CEM microwave for 4 h. Upon cobbling to roomtemperature, the reaction mixture was added to CH₂Cl₂ (50 mL) and H₂O(50 mL). The organic layer was washed with a saturated solution of NaCland dried (MgSO₄), and the solvent was removed leaving 1.3 g of a darkorange/brown oil. Preparative thin layer chromatography (TLC) on silicaeluting with 20% EtOAc/hexane gave methyl6-(4-chlorophenyl)-5-fluoro-4-((4-methoxyphenyeamino)picolinate (0.31 g,0.801 mmol, 40.1% yield) as an orange/yellow solid. Trituration withether gave a white solid (0.145 g): mp 162-164° C.; ¹H NMR (400 MHz,CDCl₃) δ 7.91 (dd, J=8.5, 1.5 Hz, 2H), 7.61 (d, J=6.0 Hz, 1H), 7.52-7.39(m, 2H), 7.25-7.13 (m, 2H), 7.07-6.91 (m, 2H), 6.30 (d, J=3.6 Hz, 1H),3.92 (s, 3H), 3.85 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −133.26; HRMS-ESI(m/z) [M+H]⁺ calcd for C₂₀H₁₆ClFN₂O₃, 386.0833; found 386.0834.

Example 4 Methyl 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinate

To a mixture of methyl6-(4-chlorophenyl)-5-fluoro-4-((4-methoxyphenyl)amino)-picolinate (0.146g, 0.377 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione(0.149 g, 0.755 mmol) in 1:1 CH₃CN/H₂O (5 mL) was added 1 M sulfuricacid (H₂SO₄, 0.4 mL). After heating to reflux for 1 h, analysis byliquid chromatography/mass spectrometry (LC/MS) showed that the reactionwas complete. The reaction mixture was added to CH₂Cl₂ (20 mL). Theorganic layer was washed with a saturated solution of NaCl and dried(MgSO₄), and the solvent was removed leaving 0.242 g of an orange oil.Preparative TLC on silica gel eluting with 20% EtOAc/hexane gave methyl4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinate (47 mg, 0.142mmol, 38% yield) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.87 (m,2H), 7.43 (m, 2H), 4.94 (br s, 2H), 3.99 (s, 3H); ¹⁹F NMR (376 MHz,CDCl₃) δ −140.86; ESIMS m/z 315.607 ([M]).

Example 5 Methyl6-(4-chlorophenyl)-5-fluoro-4-((4-oxocyclohexa-2,5-dien-1-ylidene)amino)-picolinate

A mixture of methyl6-(4-chlorophenyl)-5-fluoro-4-((4-methoxyphenyl)amino)-picolinate (0.155g, 0.400 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione(0.158 g, 0.800 mmol) in 1:1 CH₃CN/H₂O (5 mL) was stirred at roomtemperature. After 30 min the suspension of the solid ester dissolvedgiving a yellow/orange solution, then an orange solid began to form.After stirring at room temperature for 2 h, the reaction solution wasdecanted, and the orange solid was washed with 1:1 CH₃CN/H₂O (10 mL).The solid was dissolved in CH₂Cl₂ and dried (MgSO4), and the solvent wasremoved to give methyl6-(4-chlorophenyl)-5-fluoro-4-((4-oxocyclohexa-2,5-dien-1-ylidene)amino)picolinate(0.13 g, 0.316 mmol, 79% yield) as an orange solid: mp 154-156° C.; ¹HNMR (400 MHz, CDCl₃) δ 7.97 (d, J=7.3 Hz, 2H), 7.65 (d, J=5.4 Hz, 1H),7.48 (d, J=8.6 Hz, 2H), 7.36 (dd, J=10.1, 2.6 Hz, 1H), 6.87 (d, J=10.3Hz, 1H), 6.77 (dd, J=10.1, 2.1 Hz, 1H), 6.61 (dd, J=10.2, 2.1 Hz, 1H),4.02 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −145.68.

Example 6 Methyl 4-amino-6-(4-chlorophenyl)-5-fluoropicolinate

A mixture of methyl6-(4-chlorophenyl)-5-fluoro-4-((4-oxocyclohexa-2,5-dien-1-ylidene)amino)picolinate(0.074 g, 0.20 mmol) and 0.1 M H₂SO₄ (0.2 mL) in a 1:1 mixture ofCH₃CN/H₂O (2 mL) was heated to 80° C. for 1 h. After stirring at roomtemperature for 2 h, the reaction mixture was added to CH₂Cl₂ (10 mL).The organic layer was washed with a saturated solution of NaCl and dried(MgSO₄), and the solvent was removed. Preparative TLC on silica geleluting with 20% EtOAc/hexane gave methyl4-amino-6-(4-chlorophenyl)-5-fluoropicolinate (0.050 g, 0.169 mmol, 85%yield) as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.83 (m, 2H),7.45 (d, J=6.2 Hz, 1H), 7.37 (m, 2H), 4.40 (br s, 2H), 3.90 (s, 3H).ESIMS m/z 279.77 ([M−H]⁻); ¹⁹F NMR (376 MHz, CDCl₃) δ −145.11.

Example 7 Methyl 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinate

A magnetically-stirred mixture of methyl6-(4-chlorophenyl)-5-fluoro-4-((4-methoxyphenylamino)-picolinate (112mg, 0.4 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (47.3mg, 0.240 mmol) in CH₃CN (5 mL) was heated to reflux for 1 h. Uponcooling to room temperature the reaction mixture was added to EtOAc/H₂O(25 mL). The organic layer was washed with a saturated solution of NaCl(25 mL) and dried (MgSO₄), and the solvent was removed to give 0.21 g ofa light oil. Preparative TLC on silica gel eluting with 40% EtOAc/hexanegave methyl 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinate (94mg, 0.292 mmol, 73.1% yield) as an off-white solid: ¹H NMR (400 MHz,CDCl₃) δ 7.88 (m, 2H), 7.44 (m, 2H), 4.92 (br s, 2H), 3.99 (s, 3H); ¹⁹FNMR (376 MHz, CDCl₃) δ −140.86;. ESIMS m/z 315 ([M+H]⁺).

What is claimed is:
 1. A compound of Formula C

wherein R² represents C₁-C₄ alkyl.